A novel role for an old target: CD45 for breast cancer immunotherapy

• Main Authors: Annat Raiter, Oran Zlotnik, Julia Lipovetsky, Shany Mugami, Shira Dar, Ido Lubin, Eran Sharon, Cyrille J. Cohen, Rinat Yerushalmi
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2021-01-01
• Series: OncoImmunology
• Subjects: triple negative breast cancer; peripheral blood mononuclear cells; cd45; specific tumor cell killing peptide; src family of tyrosine kinases
• Online Access: http://dx.doi.org/10.1080/2162402X.2021.1929725

Breast cancer subtypes have not shown significant response to current immunomodulatory therapies. Although most subtypes are treatable, triple negative breast cancer (TNBC), an aggressive highly metastatic cancer, comprising 10–20% of breast cancers, remains an unmet medical need. New strategies are needed in order to overcome flaws in the responsiveness to current TNBC therapies. Our aims were: first, to determine the efficacy of a novel immunomodulatory peptide, C24D, on TNBC and second, to elucidate the molecular mechanism by which C24D induces immune-modulating tumor killing. Using mass spectrometry analysis, we identified CD45 as the C24D binding receptor. In vitro and in vivo TNBC models were used to assess the efficacy of C24D in reversing TNBC-induced immunosuppression and in triggering immune-modulated tumor cell killing. The CD45 signal transduction pathway was evaluated by western blot and FACS analyses. We revealed that addition of PBMCs from healthy female donors to TNBC cells results in a cascade of suppressive CD45 intracellular signals. On binding to CD45’s extra-cellular domain on TNBC-suppressed leukocytes, the C24D peptide re-activates the Src family of tyrosine kinases, resulting in specific tumor immune response. In vitro, immune reactivation by C24D results in an increase of CD69+ T and CD69+ NK cells, triggering specific killing of TNBC cells. In vivo, C24D induced CD8+ and activated CD56+ tumor infiltrated cells, resulting in tumor apoptosis. Our results should renew interest in molecules targeting CD45, such as the C24D peptide, as a novel strategy for TNBC immunotherapy.